Abstract
The p90 ribosomal S6 kinase (RSK) is a family of MAPK-activated serine/threonine kinases (RSK1-4) whose expression and/or activity are deregulated in several cancers, including breast cancer. Up-regulation of RSKs promotes cellular processes that drive tumorigenesis in Triple Negative Breast Cancer (TNBC) cells. Although RSKs regulate protein synthesis in certain cell types, the role of RSK-mediated translational control in oncogenic progression has yet to be evaluated. We demonstrate that proliferation and migration of TNBC MDA-MB-231 cells, unlike ER/PR-positive MCF7 cells, rely on RSK activity. We show that RSKs regulate the activities of the translation initiation factor eIF4B and the translational repressor PDCD4 in TNBC cells with up-regulated MAPK pathway, but not in breast cancer cells with hyperactivated PI3K/Akt/mTORC1 pathway. These results identify PDCD4 as a novel RSK substrate. We demonstrate that RSK-mediated phosphorylation of PDCD4 at S76 promotes PDCD4 degradation. Low PDCD4 levels reduce PDCD4 inhibitory effect on the translation initiation factor eIF4A, which increases translation of “eIF4A sensitive” mRNAs encoding factors involved in cell cycle progression, survival, and migration. Consequently, low levels of PDCD4 favor proliferation and migration of MDA-MB-231 cells. These results support the therapeutic use of RSK inhibitors for treatment of TNBC with deregulated MAPK/RSK pathway.
Highlights
The p90 ribosomal S6 kinase (RSK) comprises a family of four serine/threonine kinases in humans (RSK14) that are controlled by the MAPK/ERK pathway
We confirmed the inhibitory interaction of Programmed Cell Death 4 (PDCD4) proteins with eIF4A and eIF4G by immunoprecipitation assays (Figure 7D). These results indicate that RSK-mediated downregulation of PDCD4 is necessary for the translation of “eIF4A sensitive” mRNAs encoding factors involved in the proliferation, survival, and migration of Triple Negative Breast Cancer (TNBC) MDA-MB-231 cells
The over-expression of these PDCD4 proteins decreased the proliferation and migration of these cells, an effect similar to RSK inhibition or silencing, and increased their sensitivity to apoptosis induced by etoposide, as determined by the higher percentage of early and late apoptotic cells and elevated levels of cleaved PARP (Figure 1B, 2D, 2F, 7E, 7F, 7G, and 7H). These results indicate that RSKmediated down-regulation of PDCD4 facilitates the translation of mRNAs encoding factors involved in cell cycle progression and survival, and promotes proliferation, survival and migration of TNBC MDAMB-231 cells
Summary
The p90 ribosomal S6 kinase (RSK) comprises a family of four serine/threonine kinases in humans (RSK14) that are controlled by the MAPK/ERK pathway. RSKs regulate cellular growth and proliferation, cell-cycle progression, survival, and migration. All four RSKs are expressed at different levels in breast tumors and cancer cells (Human Protein Atlas; http://www.proteinatlas.org) [4]. Increased expression or activation of RSK1 and RSK2 are detected in human breast cancer tissues compared to normal breast tissues, in TNBC tissues [5,6,7]. Inhibition and/or silencing of RSK1 and RSK2 reduce proliferation, survival, migration, and invasion of breast cancer cells, especially TNBC cells, and prevent breast cancer stem cell growth, underscoring their role in breast tumorigenesis [6,7,8,9,10,11,12,13]. RSK4 shows anti-tumorigenic activity when over-expressed in TNBC www.impactjournals.com/oncotarget
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